Production of chlorine-substituted nitrogenous heterocyclic compounds



United States Patent fice 3 ,108,104 Patented Get. 22, 1963 This invention relates to a process for the production of chlorine-containing compounds of the 1,3,4-thiodiazole,

- 1,3-benzothi-azole, 1,3-benzoxazole and pyrimidine series in which the chlorine atom is in vicinal position to the :ring nitrogen.

Nitrogenous heterocyclic compounds which contain a chlorine atom in u-position to the ring nitrogen have hitherto been prepared from the corresponding hydroxy compounds by using strong chlorination agents such as phosphorus pentachloride, phosphorus oxychloride or phosphorus trichloride. It is furthermore known to o tain them from the corresponding amino compounds by the action of nitrous acid in the presence of chlorine ions. These hydroxy and amino compounds are however not very readily accessible; moreover, the prior processes are troublesome and the halogen compounds are obtained in moderate yields.

It is an object of the present invention to provide a process by which chlorine-containing compounds of the 1,3,4-thiodiazole, benzothiazole, benzoxazole and pyrimidine series in which the chlorine atom is in vicinal position to the ring nitrogen atom can be obtained from readily accessible mercapto compounds of the 1,3,4-thiodiazole, benzothiazole, benzoxazole and pyrimidine series in which the CH-group is vicinal to the ring nitrogen, the said compounds having not hitherto been used for this purpose. Another object of the invention is to prepare chlorine compounds of the 1,3,4-thiodiazole, benzothi' azole, benzoxazole and pyrimidine series in which the chlorine atom is in vicinal position to the ring nitrogen, in good yields.

We have found that chlorine-containing compounds of the 1,3,4-thiodiazole, 1,3-benzothiazole, 1,3-beuzoxazole and pyrimidine series in which the chlorine atom is ad jacent to the ring nitrogen are obtained by reacting the corresponding mercapto compounds with phosgene.

The course of the reaction is surprising because it is known that di-imidazolyl disulfides are obtained when mercapto compounds of the imidazole series are acted upon by phosgene.

The compounds serving as initial materials for the process are mercap-to compounds of the 1,3,4thidiazole, 1,3 benzothiazole, 1,3-benzoxazole and pyrimidine series in which the mercapto group is in a-position to a ring nitro gen and which thus contain, combined in a ring, the grouping:

once or twice. It is preferred to use compounds containing not more than 14 carbon atoms. Compounds of this kind include 2-mercaptothiodiazole-( 1, 3 ,4) 2-mercapto-S-methylthiodiazole-( 1,3 ,4)

2-mercapto-5-phenyl-thiodiazole-( 1,3,4) 2,5 -dimercaptothiodiazole-( 1,3,4) Z-mercaptobenzothiazole, 2-n1ercapto-6-methoxybenzothiazole, 2-mercapto-4-chlorob enzothiazole, 2-mercapto-4methyl-benzothiazole, Z-mercapto-6-phenyl-benzothiazole, 2-mercaptobenzoxazole, 2-mercap-to-5 -chlorbenzoxazo1e, Z-mercapto6-methoxybenzoxazole, Z-mercaptopyrimidine, 4-mercaptopyrimidine, 2-mercapto-4,6-dimethylpyrimidine, 2,4-dimercaptopyrimidine, 2-mercapto-4-methylpyrimidine, 2-mercapto-4-chloropyrimidine, Z-mercapto-S-methylpyfimidine and Z-mercapto-S-methoxypyrimidine.

These mercapto compounds are advantageously reacted with phosgene in the presence of solvents or diiuents. Suitable solvents or diluents are especially aliphatic hydrocarbons, aromatic hydrocarbons, aliphatic halogen hydrocarbons, aromatic halogen hydrocarbons, or ethers, for example, benzene, toluene, xylene, ligroin, chlorhenzene, chloroform, tetrahydrofurane or dioxane. The boiling range of these solvents or diluents should lie between about 35 C. and 250 C. The relative proportions of solvent and mercapto compound may vary within wide limits, for example between 1:2 and 10:1.

The reaction may be carried out at room temperature or at an elevated temperature, for example at the boiling temperature of the solvent chosen.

Mercapto compounds and phosgene should be used in about equivalent amounts, a slight excess of phosgene usually being used.

The mercapto compounds first form with the phosgene a loose (readily re-split) adduct, which in some cases can be isolated. Isolation is however neither necessary nor advantageous. The intermediate product then decomposes into the desired'chlorine compound while giving ofi carbon oxysulfide and hydrogen chloride. Decomposition of the intermediate product can be accelerated by catalysts and/or by heating; for example N- substituted acid amides of lower carboxyl-ic acids, such as dimethylformamide, N,N'-dimethylacetamide, N,N-dibutylformamide, N,N'atetramethylene-formamide, or N- alkyl substituted cyclic carboxylic acid amides (N-alkyl substituted lactams), such as N-methylpyrrolidone or N- butyl-py'rrolidone are effective as catalysts. The carboxylic acids from which these are derived usually contain 1 to 6 carbon atoms; the substituents on the nitrogen atom are alkyl groups with up to 4 carbon atoms and, when taken together, may be methylene groups of a ring with up to 8 carbon atoms. The catalysts are used in an amount of about 0.2 to 0.5% by weight, based on the amount of mercapto compound. A larger amount is however not injurious.

For Z-mercaptobenzothiazole the reaction can be formulated as follows:

\l coon o-sn c-s-oo.c1 01- \s/ S/ L H cos n01 o-o1 S/ The compounds obtainable according to the invention are valuable intermediate products, for example for the pro duction of dyes.

To carry out the process, phosgene can be led onto the mercapto compound and allowed to act thereon, but it is preferable to lead phosgene into a suspension or solution of the mercapto compound or to introduce the mercapto compound into a phosgene solution. If the phosgene is led into a solution or suspension of the mercapto compound, it is advantageous to carry out the reaction at the boiling temperature of the solvent in question. However, if the phosgene is used in a solvent and the mercapto compound added thereto, it is convenient first to mix the reactants at room temperature or at a lower temperature, for example at C. and then to heat up to the boiling temperature of the mixture, funther phosgene being introduced, if desired. Heating to more than 200 C. is however unnecessary. The reaction will proceed, if slowly,

in the cold, i.e., in the range of 0 to 30 C. The reaction can therefore be carried out in the range of 0 to 200 C., but it is preferred to apply temperatures between 30 C. and 120 C.

In general the process is carried out at atmospheric pressure. Phosgene may however be forced in at a higher pressure, for example 2 to 3 atmospheres gauge, or the reactants may be mixed at room temperature or a lower temperature and then heated in an autoclave so that an increased pressure is set up resulting from the vapor pressure of the solvent, of the phosgene and of the carbon oxysulfide formed as a reaction product.

If lower N-alkyl carboxylic acid amides are added as catalysts to accelerate the splitting off of carbon oxysulfide, these catalytically active substances may be added from the start; it is however often advantageous first to mix the reactants, i.e., the mercapto compound and the phosgene, if desired in a solvent, in the cold and only then to add the catalytically active substance. Heating the solution to about 60 to 100 C. accelerates the split ting off of carbon oxysulfide. The reaction mixture is worked up by distillation, advantageously under reduced pressure, or by steam distillation. Solid reaction products can be purified by recrystallization.

The invention is illustrated by, but not limited to, the following examples. The parts are parts by weight.

Example I A mixture of 100 parts of Z-mercaptopyrimidine and 400 parts of dioxane is heated to boiling under reflux. 100 parts of phosgene are led in in the course of 3 hours. Then the mixture is allowed to cool while leading in nitrogen and filtered. The solvent is distilled oil from the filtrate. By distillation under reduced pressure, the residue yields 76 pants (74% of the theory) of 2-chlorpyrimidine, boiling point at 10 mm. Hg 75 to 76 C., melting point 63 to 66 C.

Calculated, C H N Cl: Cl, 31.0%. Found: Cl, 31.1%.

Example 2 46 parts of 2-mercapto-4-methylpyrimidine and 250 parts of dioxane are heated to 100 C. and phosgene is lead in for four hours. Working up is as in Example 1. 35 parts (74% of the theory) of 2-chlor-4-methylpyrimidine are obtained; boiling point at 11 mm. Hg 75 to 79 C., melting point 47 to 48 C.

Example 3 50 parts of 2-mercapto-4,6-dimethylpyrimidine are introduced at room temperature into a solution of 50 parts of phosgene in 320 parts of dioxane. Then 1 part of dimethyl formamide is added and the mixture heated to boiling for 2 hours while leading in a weak current of phosgene. The mixture is Worked up as in Example 1.

43 parts (83% of the theory) of 2-cl1lor-4,6-dimethylpyrimidine are obtained; boiling point at 12 mm. Hg 97 to 99 C., melting point 29 to 31 C.

Calculated, C H N CI: Cl, 24.9%. Found: Cl, 25.2%.

Example 4 400 parts of phosgene are led at 0 C. into a mixture of 2000 parts of chloroform, 668 parts of Z-mercaptobenzothiazole and 3 parts of dimethylforma'mide. The reaction m'mture is stirred for one hour at 0 to 10 C. and

then the temperature is slowly raised to 60 C. while leading in phosgene. While further leading in a weak current of phosgene, the whole is boiled under reflux for 8 hours. The chloroform is then evaporated off under normal pressure and the residue distilled in vacuo. 548 parts (81% of the theory) of 2-chlorbenzothiazole of the boiling point 141 C. at 30 mm. Hg are obtained.

Calculated for C H NSCl: S, 18.85% Cl, 20.95%. Found: S, 18.5%; C1, 21.0%.

Example 5 151 parts of 2-mercaptobenzoxazole are introduced into a solution of 99 parts of phosgene and 1 part of dimethylformamide in 500 parts of chloroform at 0 C. The mixture is stirred for one hour at 0 to 10 C. and then slowly heated to boiling while leading in phosgene. After boiling for eight hours while leading in phosgene, the reaction mixture is worked up by distillation. 2-chlorbenzoxazole of the boiling point C. at 32 mm. Hg and the melting point 4.5 C. is obtained in an 83% yield.

Calculated for C H NOCl: N, 9.13%; Cl, 22.2%. Found: N, 9.13%; Cl, 22.8%.

Example 6 60 parts of 2,5-dimercapto-1,3,4-thiodiazole are introduced at 20 to 25 C. into a solution of 180 parts of phosgene in 400 parts of chloroform. The mixture is stirred for 2 hours. Then 2 parts of dimethylformamide are added and the whole is stirred for another 48 hours at room temperature. After filtration, the solvent is distilled off. 57 parts of 2,5-dichlor-1,3,4-thiodiazole of the melting point 66 to 68 C. are obtained as a residue. The yield is 92% of the theory. If necessary, the product may be purified by steam distillation.

Example 7 28 parts of Z-mercaptopyrimidine are introduced into a solution of 33 parts of phosgene in 200 parts of tetrahydrofurane, the temperature rising from 15 to 23 C. The mixture is stirred for 5 days at room temperature and then filtered. The solvent is distilled off from the filtrate and the residue subjected to steam distillation. From the distillate, 9 parts of 2-chlorpyrimidine with the melting point 64 to 65 C. are obtained.

We claim: 1

1. A process for the production of chloro-substituted heterocyclic compounds having not more than 14 carbon atoms and selected from the group consisting of chlorosubstituted l,3,4thiodiazoles, chloro-1,3-benzothiazoles, chloro-1,3-benzoxazoles, and chloro-substituted pyrimidines, which compounds have chlorine atom on one to two heterocyclic ring carbon atoms each of which are vicinal to a heterocyclic ring nitrogen atom, which process comprises reacting in an inert organic solvent at a temperature in the range of about 0 to 200 C. phosgene and a substantially equivalent amount of a mercapto-heterocyclic compound selected from the group consisting of mercapto 1,3,4 thiodiazoles, mercapto-benzothiazoles, mercapto-benzoxazoles and mercapto-pyrimidines, where in the mercapto-groups of said compounds are attached to 1-2 carbon atoms of the heterocyclic ring, each of which carbon atoms are vicinal to a heterocyclic ring nitrogen atom, wherein said mercapto-heterocyclic compound contains not more than 14 carbon atoms in the molecule, and

' wherein the mercapto-heterocyclic compounds bear besides said mercapto groups, no substituents other than a substituent selected from the group consisting of chlorine atoms, lower alkyl, lower aikoxy and phenyl, to replace in said reaction said mercapto-groups with chlorine atoms in said heterocyclic compounds.

2. A process as claimed in claim 1 which comprises carrying out the reaction in the presence of a small amount of N,N-dialkyl amides of alkane carboxylic acids with 1-6 carbon atoms, the alkyl substituents of said amides having from 1 to 4 carbon atoms.

3. A process as claimed in claim 1 wherein said mer- 6 capto-heterocyclic compound is mixed with phosgene at a temperature between 10 to and said mixture is heated to to C.

References filed in the file of this patent UNITED STATES PATENTS Brown et a1. Apr. 18, 1939 OTHER REFERENCES Lowy: Organic Chemistry (Seventh Edition, 1951), pages 215-6. 

1. A PROCESS FOR THE PRODUCTION OF CHLORO-SUBSTITUTED HETEROCYCLIC COMPOUNDS HAVING NOT MORE THAN 14 CARBON ATOMS AND SELECTED FROM THE GROUP CONSISTING OF CHLOROSUBSTITUTED 1,3,4-THIODIAZOLES, CHLORO-1,3-BENZOTHIAZOLES, CHLORO-1,3-BENZOXAZOLES, AND CHLORO-SUBSTITUTED PRIMIDINES, WHICH COMPOUNDS HAVE CHLORINE ATOM ON ONE TO TWO HETEROCYCLIC RING CARBON ATOMS EACH OF WHICH ARE VICINAL TO A HETEROCYCLIC RING NITROGEN ATOM, WHICH PROCESS COMPRISES REACTIN IN AN INERT ORGANIC SOLVENT AT A TEMPERATURE IN THE RANGE OF ABOUT 0* TO 200*C. PHOSGENE AND A SUBSTANTIALLY EQUIVALENT AMOUNT OF A MERCAPTO-HETEROCYCLIC COMPOUND SELECTED FROM THE GROUP CONSISTING OF MERCAPTO - 1,3,4 - THIODIAZOLES, MERCAPTO-BENZOTHIAZOLES, MERCAPTO-BENZOXAZOLES AND MERCAPTO-PYRIMIDINES, WHEREIN THE MERCAPTO-GROUPS OF SAID COMPOUNDS ARE ATTACHED TO 1-2 CARBON ATOMS OF THE HETEROCYCLIC RING, EACH OF WHICH CARBON ATOMS ARE VICINAL TO A GETEROCYCLIC RING NITROGEN ATOM, WHEREIN SAID MERCAPTO-HETEROCYCLIC COMPOUND CONTAINS NOT MORE THAN 14 CAROBN ATOMS IN THE MOLECULE, AND WHEREIN THE MERCAPTO-HETEROCYCLIC COMPOUNDS BEAR BESIDES SAID MERCAPTO GROUPS, NO SUBSTITUTENTS OTHER THAN A SUBSTITUENT SELECTED FROM THE GROUP CONSISTING OF CHLORINE ATOMS, LOWER ALKYL, LOWER ALKOXY AND PHENYL, TO REPLACE IN SAID REACTION SAID MERCAPTO-GROUPS WIH CHLORINE ATOMS IN SAID HETEROCYCLIC COMPOUNDS. 